In the present study, we show that the extracellular addition of nicotinamide adenine dinucleotide (NAD(+)) induces a transient rise in [Ca(2+)](i) in human monocytes caused by an influx of extracellular calcium. The NAD(+)-induced Ca(2+) response was prevented by adenosine triphosphate (ATP), suggesting the involvement of ATP receptors. Of the two subtypes of ATP receptors (P2X and P2Y), the P2X receptors were considered the most likely candidates. By the use of subtype preferential agonists and antagonists, we identified P2X(1), P2X(4), and P2X(7) receptors being engaged in the NAD(+)-induced rise in [Ca(2+)](i). Among the P2X receptor subtypes, the P2X(7) receptor is unique in facilitating the induction of nonselective pores that allow entry of ethidium upon stimulation with ATP. In monocytes, opening of P2X(7) receptor-dependent pores strongly depends on specific ionic conditions. Measuring pore formation in response to NAD(+), we found that NAD(+) unlike ATP lacks the ability to induce this pore-forming response. Whereas as little as 100 muM ATP was sufficient to activate the nonselective pore, NAD(+) at concentrations up to 2 mM had no effect. Taken together, these data indicate that despite similarities in the action of extracellular NAD(+) and ATP there are nucleotide-specific variations. So far, common and distinct features of the two nucleotides are only beginning to be understood.